J. Org. Chem. 1991,56,2311-2317 (500pg, 1.9 rmol), TBHP (4.0 M in CH2C12,50 pL), benzene (1.0 mL), and subsequent purification by HPLC. The IR and 400MHz 'H Nh4R spectra and HPLC retention times of both sample were identical with those of the sample prepared by the stepby-step method. Acknowledgment. We are grateful to Professor Etsuro Kurosawa and Dr. Teruaki Suzuki of Hokkaido University for the generous gift of a sample of natural teurilene (1) and for fruitful discussions. RedStry NO. 1,96304-92-6; 29,116216-69-4; 31,123908-75-8; 33,123908-76-9; 34,132298-82-9; 35,123908-77-0; (-)-36,8218873-6; 36 tosylate, 121401-06-7; (-)-37,76985-25-6; 37 diol hylate,
2311
132341-93-6; (+)-38,121400-91-7; 39,116216-77-4; 40,116216-7&5; 41,121429-28-5; 42,116216-79-6; 42 TBDMS ether, 121400-96-2; 43,121400-97-3; 43 aldehyde, 121400-98-4; 44,121400-92-8; 45, 121400-99-5; 45 chloride, 121401-00-1; 46, 121400-93-9; 47, 121429-29-6;48, 132298-83-0; 49, 121400-94-0; 50, 121400-95-1; 51,121429-30-9; 52,121401-03-4; 53,121401-04-5; 54,121401-05-6; 55,109307-91-7; 55 THP ether, 132298-84-1; 56,132298-85-2; 56 aldehyde, 132298-86-3; (*)-57,132341-94-7; (f)-58,13229&87-4; ( f ) - 5 9 , 132298-88-5; 60, 123908-78-1; 61, 122554-78-3; 62, 132298-89-6;63, 122554-81-8; 64, 122554-82-9;65, 122554-84-1; 66,124018-82-2; CH3C(PPh&CO2Et, 5717-37-3; geraniol, 106-24-1.
Supplementary Material Available: 'H NMR spectra of
1,33-3&3,43-49,51,52, and 56-66 (30pages). Ordering information is given on any current masthead page.
Stereoselectivities of Intramolecular Diels-Alder Reactions. Formation of the Taxane Skeleton Kunio Sakan,lVP Douglas A. Smith,**2a*b Stefan A. Babirad,Pic Frank R. Fronczek,2dand K. N. Houk**2e Department of Chemistry, Carnegie-Mellon University, Pittsburgh, Pennsylvania 15213, Department of Chemistry, University of Toledo, Toledo, Ohio 43606, 3M Company, St. Paul, Minnesota 55144, Department of Chemistry, Louisiana State University, Baton Rouge, Louisiana 70803, and Department of Chemistry and Biochemistry, University of California, Los Angeles, California 90024 Received August 6 , 1990
The stereodirectingeffect of an alkyl (Me) group on the diene and/or dienophile on the intramolecularDiels-Alder reaction leading to the formation of an eight-membered ring has been studied under both thermal and Lewis acid catalyzed cyclization conditions. The synthesis and cycloaddition reactions of tetraenes 2a-d, leading to the formation of the taxane skeleton, is described. Selectivity is shown to vary under thermal conditiotu depending upon substitution pattern, while the catalyzed cycloaddition invariantly gives the cis-fused product.
Introduction The taxane diterpenes3 such as tax01 (la)and cephalomannine (lb)have received much attention over the past decade. These materials have shown significant antileukemic and tumor-inhibitory properties? Structurally, the taxanes have posed may challenges to the organic chemist. The unusual tricyclic carbon framework that contains a bridgehead olefin, a sterically congested eight-membered ring system, and a bicyclo[5.3.l]undecene system trans fused to a cyclohexane ring has not yet yielded to a total synthesis of these complex molecules, although a synthesis of the simplest member of this family of compounds, taxusin, has appeareda6' Numerous synthetic approaches to the taxane skeleton ring system have been reported with the earliest entry dating back to 1974.% (1) Deceased 12 January, 1984. (2) (a) Carnegie-Mellon University. (b) University of Toledo. (c) 3M Company. (d) Louisiana State University. (e) University of California a t Loe Angeles. (3) (a) Lythgoe, B. The Alkaloids, Academic Press, New York, 1968, p 597. (b) Nakanishi, K.; Goto, T.; Ito, S.; Natori, S.; Nozoe, S. Natural Products Chemistry; Kodansha-Academic Preee: Tokyo, 1974; Vol. 1, p 281. (c) Miller, R. W. J. Not. Prod. 1980,43, 425. (4) (a) Wani, M. C.; Taylor, H. L.; Wall, M. E.; Coggon, P.; McPhail, A. T. J. Am. Chem. SOC.1971,93,2325. (b) Smith, C. R., Jr.; Powell, R. G.; Mikolajczak, K. L. Cancer Treat. Rep. 1976,60,1157. (c) Schiff, P. B.; Fant, J.; Horwitz, S. B. Nature (London) 1979,277,665. (d) Miller, R. W.; Powell, R. G.; Smith, C. R., Jr. J . Org. Chem. 1981,46, 1469. (e) Manfredi, J. J.; Horwitz, S. B. Pharmacol. Ther. 1984,25, 83. (5) (a) Kumazawa, S.; Nakano, Y.; Kato, T.; Kitahara, Y. Tetrahedron Lett. 1974,1757. (b) Kato, T.; Takayanagi, H.; Suzuki, T.;Uyehara, T. Tetrahedron Lett. 1978,1201. (c) Swindell, C. S.; Britcher, S. F. J. Org. Chem. 1986,51,793.
The question of the construction of the basic carbon framework has been addressed via a biogenetical consideration, extensive chemical modifications of camphor: a skeletal reorganization of the bicyclo[2.2.2]octane system via an anionic oxy-Cope reaction,' several photolysis processes? novel rearrangements and fragmentation routes! annulation strategies,l0intercalation of enediol silyl eth~~~~~~~~
(6) (a) Shibuya, H.; Shmji, T.; Yamamoto, Y.; Murakawa, K.; Takagi, K.; Kurokawa, N.; Kitagawa, I. Chem. Abstr. 1982, 96, 21806Ov. (b) Inouye, Y.; Fukaya, C.; Kakisawa, H. Bull. Chem. SOC. Jpn. 1981, 54, 1117. (c) Kitagawa, I.; Shibuya, H.; Fujioka, H.; Kajiwara, A; Yamamoto, Y.;Takagi, A. Chem. Abstr. l980,92,198568g. (d) Kitagawa, I.; Shibuya, H.; Fujioka, H.; Kajiwara, A.; Tsujii, S.; Yamamota, Y.; Takagi, A. Chem. Lett. 1980, 1001. (e) Holton, R. A. J. Am. Chem. SOC.1984,106,5731. (0Holton, R. A.; Juo, R. R.; Kim, H. B.; Williams, A. D.; Harusawa, S.; Lowenthal, R. E.; Yogai, S. J. Am. Chem. SOC. 1988,110,6558and references therein. (7) (a) Martin, S. F.; White, J. B.; Wagner, R. J. Org. Chem. 1982,47, 3190. (b) White, J. B. Ph.D. Thesis, University of Texas at Austin, 1983. (c) Wagner, R. Diss. Abstr. Int. B 1987, 48,447. (8) (a) Benchick-le-Hocine, M.; Do Khac, D.; Fetizon, M. Synth. Commun. 1987, 17, 913. (b) Berkowitz, W. F.; Amarasekara, A. A.; Perumattam, J. J. J. Org. Chem. 1987,52, 1119. (c) Berkowitz, W. F.; Perumattam, J.; Amaraaekara, A. Tetrahedron Lett. 1985,26,3665. (d) Neh, H.; Blechert, S.; Schick, W.; Jansen, M. Angew. Chem., Int. Ed. Engl. 1984, 23, 905. (e) Cervantes, H.; Do Kahc, D.; Fetizon, M.; Guir, F.; Beloeil, J.-C.; Lallemand, J.-Y.; Prange, T.Tetrahedron 1986,42,3491. (0Winkler, J. D.; Lee,C.-S.;Rubo, L.;Muller, C. L. J. Org. Chem. 1989, 54, 4491. (9) (a) Swindell, C. S.; Patel, B. P.; deSolms, S. J. J . Org. Chem. 1987, 52, 2346. (b)Lin, J.; Nikaido, M. M.; Clark, G. J. Org. Chem. 1987,52, 1988, 3745. (c) Funk, R. L.;Daily, W. J.; Parvez, M. J. Am. Chem. SOC. 53,4141. (d) Trost, B. M.; Hiemstra, H. Tetrahedron 1986,42,3323. (e) Nagaoka, H.; Ohsawa, K.; Takata, T.; Yamada, Y. Tetrahedron Lett. 1984,25,5389.
0022-3263/91/1956-2311$02.50/00 1991 American Chemical Society
Sakan et al.
2312 J. Org. Chem., Vol. 56, No. 7, 1991 em," several unique cyclization methods,12 and numerous intramolecular Diels-Alder (IMDA) appro ache^.'^ All of these methodologies can be further classified in a broad sense, namely, formation of the eight-carbon B ring indirectly via ring expansion or, conversely, via direct ring closure. This latter approach has proven to be difficult as is generally found for the formation of medium rings.'"
Scheme I'
8
1:I
IO
la R-Ph Ib R=CM&HMe
We have reported our systematic model studies of the Lewis acid catalyzed cycloadditions of internally activated trienes that show this to be a viable route for the stereoselective formation of systems containing seven-, eight-, and nine-membered rings.14J6 Sakan has reported the synthesis of the taxane model system 3d using this technology (eq 1).'%J6The thermal and catalyzed reactions
13
Key: A (1)NaOEt/EtOH, 25 "C, (2) CHpCHCH2Cl,0 "C, (3) KOH/H20, 0 "C, (4) 10% KOH/ethylene glycol, 135 "C; B (1) MeMgBr/EtO, 0 "C,(2) MgSO,/pentane; C CHaC02CHCH2/ AlCl,/PhH, 25 "C, D (1) LAH/THF, 0 O C , (2) MsCl/EbN/THF, -25 "C,(3) NaI/NaCN/Dh&O, 73 "C, (4) DIBAL/CH2C12,-78 "C.
I
2d
3d
of 2d proceeded in high yield to give the trans- and cisfused products, respectively. This result was surprising, since catalysis of the Diels-Alder reaction normally enhances but does not reverse stereoselectivity. The stereodirecting effects of alkyl substituents located on the diene and dienophile have been investigated in simple systems leading to cyclooctanes 5 (eq 2).16 In this
4
Yb
9a
6
5
paper, we report an extension of this work to the b a n e diterpene system. The effects of methyl substituents on the stereochemical outcome of the IMDA reaction of the four substrates 2a-d under both thermal and Lewis acid catalyzed conditions have been investigated, and the results are described in the following text. (lO).(a) Swindell, C. S.;Petal, B. P. Tetrahedron Lett. 1987,28,5275.
(b) Swmdell. C. S.: desolms, S. J Tetrahedron Lett. 1984, 25, 3801.
.(11) Troet, B. M:; Fray, J..Tetrahedron Lett. 1984,25,4605. (12)(a) Kende, A. S.;Johnson, S.; Sdilippo, P.; Hodges, J. C.; Jungheim, L. N. J. Am. Chem. SOC.1986,108,3513.(b) Ohtsuka, Y.;Oishi, T. Tetrahedron Lett. 1986,27,203. (13)(e) Sakan,K.; Craven, B. M. J. Am. Chem. SOC.1988,106,3732. (b)Bonnert, R. V.; Jenkins, P. R.J. Chem. SOC.,Chem. Commun. 1987, 1540. (c) Brown, P.A.; Jenkins, P. R. J. Chem. SOC.,Perkin Trans. 1 1986,1303. (d) Gilman, J. W. Dies. Abstr. Znt. B 1986,47, 1060. (e) Wender, P. A.; Snapper, M. L. Tetrahedron Lett. 1987,28,221. (0Shea, K. J.; Davis, P. D. Angew. Chem., Int. Ed. Engl. 1983,22,419.(g) Shea, K J.; Gilmnn, J. W.; Hnffner, C. D.; Dougherty, T. K. J. Am. Chem. Soc. 1986,108,4953.(h) Shea, K. J.; Hnffner, C. D. Tetrahedron Lett. 1988, 29, 1367. (14)(a) Smith,D. A.; Snkan, K.; Houk, K. N. Tetrahedron Lett. 1986, 27,4877. (b) Smith, D. A. Ph.D. Thesis, Carnegie-Mellon University, 1985. (15)Sakan,K.; Smith, D. A. Tetrahedron Lett. 1984,25,2081. (16)Craven, B. M.;Saknn, K. Acta Crystallogr., Sect. C 1983,C39, 1556.
Figure 1. X-ray crystal structures of 3a-a-cis and 3a-8-trans.
Results and Discussion A convenient starting material for the targeted tetraenes 2a-d is the commercially available 4-carbethoxy-3methyl-2-cyclohexen-1-one(6), cf. Scheme I.13a*17*18 Treatment of 6 with sodium ethoxide in ethanol a t room temperature followed by the addition of allyl chloride gave the a-alkylated keto ester, 7. Saponification of the ester moiety in aqueous KOH a t 0 O C and subsequent decarboxylation of the resultant acid using 10% KOH in ethylene glycol afforded the desired 2-allyl-3-methyl-2cyclohexen-1-one (8) in 65% overall yield. A 1:l mixture of 1-methyl-3-methylene-2-(2-propenyl)cyclohexene (9a) and its structural isomer cyclohexadiene 9b was formed when ketone 8 was treated with methyl magnesium bromide at 0 "C followed by dehydration with anhydrous magnesium sulfate in pentane a t room temperature. Attempts to convert the cyclohexene 9b to 9a under pyridinetosylate conditions proved fruitless. The mixture of trienes 9a,b was then dissolved in dry benzene and reacted with vinyl acetate in the presence of aluminum chloride to yield the bicyclo[2.2.2]octene ring system 10 in 60% overall yield from enone The 65% yield for the cycloaddition step is due to isomerization of the starting materials 9 during cycloaddition. The reduction of ester 10 with lithium aluminum hydride in THF followed by activation of the primary alcohol provided the mesylate 11, which underwent a Finkelstein-type reaction with sodium iodide. Displacement of the primary iodide with sodium cyanide in DMSO at 73 (17)(a)Johneon, W. 5.;D a w n , M. I.; Ratcliffe, B. E. J. Org. Chem. 1977,42,153. (b) For an nnalogy, we: Inukni, T.; Kojima, T. J. Org. Chem. 1967,32,869. (18)Smith, L. I.; Rounult, G. F. J. Am. Chem. Soc. 1943,88,631.
Formation of the Taxane Skeleton
J. Org. Chem., Vol. 56, No. 7, 1991 2313
Scheme IIo
Table I. Stereochemical Outcome of the Cycloadditions of 2 and 4 O a-trans/ a-trans a-cis a-cis @-trans @-cis a/@ 17 64 0.21 19 9 4.26 2a thermal 0 0 catalyzedb 0 97 36 49 0.73 15 0 5.67 2b thermal catalyzedb 0 97 0 0 38 27 1.40 12 13.5 2.57 2c thermal catalyzed 0 80 0 15' 2d thermald 70 0 85 0 0 catalyzed 19 34 0.56 4arJ thermal 0 69 catalyzed 4buJ thermal 11.4 8.6 1.33 catalyzed 7 55 0.13
B
14 a: R1 = H, 13% b R1 =Me,79%
IS . :R I - H . 4 7 8 b R1-Mc,34%
16 . :RI = Rz = H
Values given are in absolute percent yield; ratios are untiless. bOnly one cycloaddition product was observed. The structural assignment of this product is tentative. dAn unidentified minor product accounted for 15-20% of the total yield of this reaction. See text for a discussion. e Reference 15. 'The designations a and @ have no meaning for these compounds.
b R1 - M e , R Z = H
16 c: R1 = H , R 2 = M e
2 e: RI = H. R2= Me 35%
d: R 1 Rz =Me
d: R 1 = Rz = Mc 33%
-
'A PhaPCR1C02Me/PhH/dark,25 "C; B (1) OsO,/THF, -60 28 "C, (2) H2S/THF, ) "C, (3) NaI04/3:1 MeOH/H20, 0 "C; C 25 "C; D CH,C(CH,)MgBr/THF, -78 OC; CH,CHLi/THF, -78 E (1) TBSCl/DMAP/dark, 25 "C, (2) DIBAL/CH2CI2,-78 OC, (3) PDC/DMF, 0 OC, (4) n-BuLi/Ph3PCHSBr/THF, 25 OC, (5) nBu4NF/THF, 25 "C, (6) (i) TFAA/DMSO/CH2C12, -78 OC, (ii) EhNi-Pr, -78 0 OC.
-
-
"C gave the nitrile 12. Treatment of 12 with DIBAL in dichloromethane gave aldehyde 13 in 95% yield from 10. At this stage, our route was set to diverge to produce the Diels-Alder substrates 2a-d, which contain the various substitution patterns. These substrates incorporate the bicyclo[2.2.2]octene system in order to overcome entropic problems common to IMDA reactions in which the diene and dienophile are separated by a chain of five or more atoms by rigidly positioning C1, C2, C3, C4, and C8 (Figure l).13afJ0 This locks the A-ring synthon into the boat conformation (which is known for the natural taxanesm) and eliminates free rotation about five single bonds. The bicyclooctane also serves as a masked C2 geminal methyl group, a structural feature that is expected to disfavor cyclization.21 This system can be considered synthetically equivalent to the taxane A ring, provided appropriate functionality exists at either C9 or C10. The stereochemistry observed at C3 is correct for the natural product. In the event, Wittig reaction of aldehyde 13 with either methyl (triphenylphosphorany1idene)acetate or ethyl (triphenylphosphorany1idene)acetate in dry benzene gave the olefinic products 14a (R' = H)or 14b (R' = Me) in 73 and 79% yield, respectively (Scheme 11). Osmylation of the C1 allyl moiety followed by periodate cleavage of the resultant diol gave the aldehydes 15a (47%) and 15b (3470)
Chain extension on the C7 aldehyde function was accomplished by treatment with vinyllithium or allylmagnesium bromide in THF to yield an epimeric mixture of allyl alcohols 16a-d. Protection of the C7 alcohol as its silyl ether followed by DIBAL reduction of the C4 ester moiety, PDC oxidation, and Wittig olefination with methyltriphenylphosphonium bromide gave the conjugated diene system of 17a-d in 46% overall yield from 15a-b. Deprotection of the C7 silyl ether with tetrabutylammonium fluoride followed by oxidation using trifluoroacetic anhydride in DMSO/CH2C12provided the C7 keto tetraenes 2a-d in 60% yield with the appropriate substitution patterns a t C6 and C14. The cycloaddition studies using 2a-d were carried out under both thermal and Lewis acid catalyzed conditions. The stereochemical outcome of these reactions is summarized in Table I. With one exception (3c-&cis, vida infra), each product was isolated in pure form and resubjected to the reaction conditions employed; adducts were found to be configurationally stable. Each product obtained had the taxane skeleton. This was not unexpected, since (1)cycloaddition of the diene to the activated, a,@unsaturated ketone is more likely than the cycloaddition to the inactivated tetrasubstituted olefin of the bicyclo[2.2.2loctene system and (2) the preferred regioselectivity of the reaction between 1-alkyl or 1,2-dialkylbutadienes with electron-deficient alkenes unites the unsubstituted termini of the two reactants.n We have classified the four possible stereoisomers of the products 3 as a or p , depending on whether the hydrogen originating at the internal diene terminus (H5) is down or up, respectively, and as cis or trans, according to the nature of the B/C ring fusion in the taxanes. By use of this nomenclature, naturally occurring taxanes have the a-trans stereochemistry.
.
(19) The rigid group principle statee that incorporation of torsionally rigid groupa into acychc precureors encourages the formation of medium rings for statistical reasons. For examples, refer to: (a) Baker, W.; Banks, R.; Lyon, D. R.; Maim, F. G.J. Chem. SOC.1945, 27. (b) Baker, W.; McOmie, J. F. W.; Ollis, W. D. J. Chem. Soc. 1951, 200. (c) Vogtle, F.; Neumann, P. Synthesis 1979,86. (20) (a) Woods, M.C.; Chiany, H. C.; Nakadana, Y.; Nakanishi, K. J. Am. Chem. Soc. 1968,90,622. (b) Castellono, E. E.; Hodder, 0. J. R. Acta Crystallogr., Sect. E . 1973, E29,2566. (21) Boeckman, R.; KO,S. S . J. Am. Chem. SOC.1982,104,1033and references therein.
3a
3b
3c
Cycloaddition of 2 s (R'= R2= H). The reaction of 2a in benzene at 140 OC gave a quantitative yield of three products in a ratio of 64:1917.23a Comparison of the 'H (22) Fleming, I. Frontier Orbitak and Organic Chemistry Reactions; John Wiley & Sons: New York, 1976; pp 86-181.
Sakan et al.
2314 J. Org. Chem., Vol. 56, No. 7, 1991 NMR signals assigned to HS and H8' was diagnostic. Under catalyzed conditions (AlC13 or Me2A1C1,benzene, room temperature) a single product idential with the Y j o r thermal product was formed quantitati~ely.~~' The structures of the two major components from the thermal reaction were determined by single-crystal X-ray analysis (Figure 1). The predominant product had the 3a-a-cis stereochemistry, while the second most abundant. thermal product was 3a-@-trans. The least abundant product was determined to be 3a-a-trans by base-catalyzed interconversion with the major product. Since H6 (cf. Figure 1)is the only epimerizable proton, the major and minor products must have the same stereochemistry at C5. An equilibrium ratio of 3961 for 3a-a-cis/3a-a-trans was obtained upon treatment of either compound with NaOMe in MeOH.XlbWhile the cis isomer is formed more readily during the cycloaddition, the trans-fused product is thermodynamically favored by 0.3 kcal mol-'. This parallels our earlier results (Table I).l4J6'H NMR data obtained at 300 and/or 600 MHz were obtained for all three thermal reaction products and were of assistance for the structure determination of the more highly substituted analogues described in the following text. Cycloaddition of 2b (R' = Me, R2 = H).The cycloaddition reactions were carried out under conditions identical with those used for 2a. The thermal reaction again provided a quantitative yield of three compounds in a ratio of 4936:15.X18The catalyzed reaction formed a single product quantitatively, identical with the major thermal product. This compound was identified as 3b-acis by comparison of the 'H NMR spectrum to the spectra of the cycloadducts 3a. The assignment was confirmed by chemical correlation with 3 d - a - ~ i s ' ~ as ~ * follows. '~ Treatment of 3b-a-cis with KOt-Bu in THF followed by methyl iodide provided 3d-a-cis, identical by 'H NMR and TLC with an authentic sample. Treatment of 3b-a-truns, described in the following text, under identical conditions resulted only in recovery of starting material. Presumably, proton abstraction by the bulky base is not possible due to steric hindrance in this isomer. This issue is being addressed as part of ongoing molecular modeling studies. The second most abundant thermal cycloadduct was shown to be epimeric with 3b-a-cis by NaOMe-catalyzed epimerization. The equilibrium ratio of 68:32 for 3b-acis/3b-a-trans shows a reversal of the relative stabilities of cis and trans compounds compared to the all-hydrogen 3a. Interestingly, this increased relative stability of 3ba-cis is not reflected by a faster rate of formation. The ratio of 3b-a-cis/3b-a-trans is 5&42 from the thermal cycloaddition and 68:32 from equilibration, whereas the corresponding ratios for 3a are 79:21 and 39:61, respectively.XlbThis again parallels the results observed for the formation of the bicyclo[6.4.0]dodecene system.14J6 The structure of the least abundant thermal cycloadduct was shown to be 3b-8-trans by partial elucidation of the single crystal structure (Figure 2). Crystals are monoclinic, P2i,c, with two independent molecules in the asymmetric unit. One molecule is disordered, and at the present state of refinement, R = 0.23, a satisfactory model has not been found. The second molecule appears well-ordered,and this portion establishes the stereochemistry of the compounds. Cycloaddition of 2c (R' = H,R2 = Me). The most complex results were obtained from 2c. This compound is less reactive than 2a or 2b," the thermal cycloaddition (23) (a) Determined by lH NMR at 300 MHz. (b) The equilibrium ratio wan determined by integration of the well-resolved multipleta assigned to olefinic proton H15. (c) Determined by isolation.
el7
6 d Figure 2. X-ray crystal structure of 3b-P-trans.
was carried out at 160 "C in toluene containing 5 equiv of trimethyl borate to suppress byproduct formation.'% A 90% yield of four cycloadducts was obtained from the thermal reaction in a ratio of 42:30:15:13,2k while the Me2AlC1-catalyzedreaction proceeded in 95% yield to give an 84:16 ratio23eof two products. The two predominant products of the thermal reaction were readily identified by 'H NMR as 3c-a-trans (42%) and 3c-a-cis (30%). Coupling patterns and selective decoupling of the olefin protons were also used to assign the least abundant product as 3c-P-trans. The fourth product, which was unstable after isolation, was tentatively assigned as 3c-&cis on the basis of its 600-MHz 'H NMR spectrum. The major product of the catalyzed reaction was 3c-acis. This was chemically correlated by independent synthesis from 3a-a-cis by treatment with KOt-Bu in THF followed by methyl iodide. Again, treatment of the a-trans epimer under these conditions gave only recovered starting material. The minor catalyzed product was identical by 'H NMR and TLC with the tentatively assigned 3c-a-cis. Cycloaddition of 2d (R' = R2 = Me). As described earlier,lhJ6 the thermal cycloaddition of 2d gave a 4:l mixture of products from which 3d-a-trans was isolated in 70% yield while the catalyzed reaction provided 3c-a-cis in 85% with just a trace (i.e., < 5 % ) of minor product observed by 300-MHz 'H NMR. In neither case was the minor product isolated or identified. Trends i n Cycloaddition Stereoselectivity. Table I summarizes the cycloaddition reaction results. Under thermal cyclization conditions, placement of a methyl group on the conjugated diene of 2 increases the selectivity for a over 8 slightly and doubles the a-trans to a-cis ratio (cf. 2a to 2b and 2c to 2d). This is in qualitative agreement with the effect observed during formation of the bicyclo[6.4.0]dodecene system 5 (cf. eq 2). Placement of a methyl group on the diene of 4 increases the trans selectivity slightly (cf. 4a to 4b). Methyl group substitution on the dienophile of 2 (cf. 2a to 2c and 2b to 2d) decreases formation of a relative to /3 products by 40%. However, the selectivity for a-trans over a-cis increases significantly;the (24) Similarly,substrates leading to the bicyclo[6.4.0]ddecene system 5 containing a bridgehead methyl group were also less reactive. Neither
i nor ii gave any intramolecular cycloadduct under thermal conditione, while Lewis acid catalyais required a temperature of 50-55 O C in order to proceed at an appreciable rate.
i
ii
Formation of the Taxane Skeleton
J. Org. Chem., Vol. 56, No.7, 1991 2315
troleum ether/ether (3:1), R 0.53) indicated complete reaction. trans/ciS ratio is more than five times greater than for the The reaction was diluted wid water (100 mL) and extracted into unsubstituted system. Substitution of a methyl group on a solvent mixture of 1:2 CHzClz/petroleum ether (3 X 100 mL). both the diene and dienophile has a synergistic effect. The organic layers were combined and dried over Na#04, filtered, There is no trend to analyze in the catalyzed cases. With and concentrated. Purification by flash chromatography on silica the exception of a minor product obtained from 2c, all the left 21.4 g (65%) of 8. catalyzed reactions give exclusively products with a-cis l-Methyl-3-methylene2-(2-propenyl)cyclohexene (9b)and geometry. This is in contrast to the bicyclo[6.4.0]dodecene l,3-dimethyl-2-(2-propenyl)-l,3-cyclohexadiene (9a)'. A soseries, in which substitution of a methyl group for a hylution of enone 8 (3.87 d,25 mmol) in ether (50 mL) was treated drogen on either the diene or dienophile caused an increase with methylmagnesium bromide (11.5 TL, 2.3 M) at 0 "C. The reaction was warmed to room temperature and stirred for 1h at in the amount of trans-fused product formed.15 In these which time TLC (petroleum ether/ether 2:l) indicated product cases, the position of the methyl substituent made little formation. The reaction was cooled to ice temperature and difference to the change in stereoselectivity, and the comquenched with aqueous sodium tartrate (0.5 mL). The crude bined effect of the two substituents was additive, not addition product was extracted into 2:l CHzClz/petroleumether synergistic. The high cis selectivity of Lewis acid catalyzed (3 x 50 mL). The combined organic layers were washed with intramolecular Diels-Alder reactions of internally activated saturated brine, dried over Na2S04,filtered, and concentrated. dienophiles has been d o c ~ m e n t e d . ~ ~ * J ~ ~ ~ ~ ~ ~The crude material was then taken up in pentane (200 mL) and The preference for H5 CY stereochemistry appears to be treated with anhydrous MgSO1. The mixture was stirred at room a unique feature of the skeleton of 3. Molecular mechanics temperature for 10 h after which time TLC (petroleum ether, R studies are in progress and will be reported in due course. 0.91) indicated complete dehydration. The solution was filtered
Experimental Section" All reactions were performed in oven-dried glassware under dry argon. The solvents benzene, toluene, and tetrahydrofuran were distilled from benzophenone ketyl and methylene chloride from calcium hydride immediately prior to use. R values refer to TLC, carried out on 0.25-mm silica gel plates (herck F254), with the same eluant indicated for the column chromatography. Ultraviolet light, iodine vapor, and 5% phosphomolybdic acid in 95% ethanol were used to visualize compounds. Chromatographic separations were performed by using flash columns with Merck Kieselgel60 (230-400 mesh) silica gel.n Yields reported are for isolated, purified materials. NMR spectra were recorded on an IBM NR-80 (lH, 80-MHz), a Bruker WH-300 (lH, 300MHz), or the Carnegie-Mellon University 600 (lH, 600-MHz) spectrometer. Spectra were taken in CDC13, using the residual solvent peak at 7.24 ppm as the internal standard unleqotherwise noted. Chemical shifts are reported in ppm, coupling constants in hertz. The following abbreviations are used: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), and b (broad). 2-Allyl-3-methyl-2-cyclohesen-lone (8). A mixture of ethanol (150 mL) and sodium (5.4 g, 0.23 mol) was refluxed under argon until all of the sodium had been consumed. The resulting solution was cooled to 0 OC (icewater), and Hagemann's esterz1 (6; 36.4 mL, 0.22 mol) was added dropwise. The reaction was warmed to room temperature and stirred for 30 min. The dark enolate anion solution was then cooled to 0 OC (ice-water), and 0.32 mol) was added dropwise. The reaction allyl chloride (26 d, was allowed to warm slowly to ambient temperature and stirred for 25 h. TLC (petroleum ether/ether (l:l),R, 0.72) indicated complete consumption of 6. The reaction was cooled to ice temperature and saponified with 5 N KOH (50mL) and stirred 3.5 h. The mixture was diluted with water (250 mL) and extracted into CHC1, (4 x 50 mL). The aqueous layer was made acidic (pH -1) by the addition of concentrated HCl (20 mL) and then extracted with CHC13 (3 x 100 mL). The combined organic washings were dried over Na804,filtered, and concentrated. TLC (10% MeOH/CHC13)of the crude acid showed one spot with R 0.38. The acid was then taken up in ethylene glycol (35 mL), and powdered KOH (4 g, 0.07 mol) was added. The mixture was heated under argon for 2 h at 135 OC at which time TLC (pe(25) Ciganek, E. Organic Reactions; John Wiley & Sons: New York, 19W,pp 1-374. (26) Due to the untimely death of the principle investigator, the subsequent dispersion of the remaining researchers,and the amount of time elapeed since the bulk of this synthetic work WBB accomplished, we have been unable to locate all of the pertinent spectroecopic and analytical data for the compounds described herein. We feel, however, and Professor Heathcock has concurred, that because of the divergent nature of this synthesis and the availability of NMR and crystallographic data for the cycloaddition substrates and producta, that the identity of the synthetic intermediates hae been sufficiently established to meet the criteria of this
journal.
(27) Still, W.; Kahn,M.; Mitra, A. J. Org. Chem. 1978,43, 2923.
to remove the magneaium sulfate, and the filtrate was concentrated to leave 3.5 g (95%) of 9a and 9b in a 1:l product ratio. Bicyclo[2.2.2]octene 10. To a benzene (140 mL) solution of vinyl acetate (5 mL, 54 mmol) and 0.183 N AlC13 in ether (7.5 mL) stirring at room temperature under argon was added a solution 9a and 9b (4.26 g, 28.7 mmol) in benzene (16 mL) over 5 h. The reaction was stirred for 18 h until TLC (petroleum ether/ether ( l o l ) , R, 0.65) indicated complete consumption of 9a,b. The reaction was quenched by the addition of aqueous sodium tartrate, and the crude product 10 was extracted into petroleum ether (2 X 100 mL). The organic layer was dried over NazS04, filtered, and concentrated. Purification by flash chromatography on silica (petroleum ether/ether (301)) left 4.38 g (65%) of 10. Preparation of Aldehyde 13. To stirred solution of 10 (3.76 g, 16.1 mmol) in THF (70 mL) at 0 OC was added lithium aluminum hydride (1.0 M, 20 mL). The reaction was stirred at ice temperature for 30 min at which time the disappearance of 10 was noted by TLC (petroleum ether/ether (l:l),RlO.61). Celite (6 g) was added to the reaction followed by the addition of aqueous Na301. The resulting mixture was stirred at ambient for 15 min, and the insoluble inorganics were removed by vacuum filtration. The filter pad was exhaustively washed with THF until no product was observed in the washes by TLC. The combined filtrates were concentrated and the residue azeotroped twice with toluene (ca. 10 mL each). The resultant crude alcohol was obtained in quantitative yield and taken up in THF (70 mL). The THF solution was cooled to -25 "C and treated with triethylamine (4.6 mL, 33 mmol) followed by methanesulfonyl chloride (1.37 mL, 17.7 mmol). The reaction was complete within 10 min as judged by TLC (petroleum ether/ether (21))and quenched with water. The insoluble precipitates were removed by filtration, and the organic fitrate was dried over NaZSO4,filtered, and concentrated to leave crude mesylate 11. To a solution of mesylate 11 in DMSO (39 mL) was added NaI (1.2 g 8.0 mmol) and NaCN (7.7 g, 0.16 mol). The reaction was then heated in the dark at 73 OC for 44 h. The reaction was cooled to room temperature and diluted with water (300 mL) and the product extracted with petroleum ether (3 X 150 mL). The organic layers were combined and dried over Na2S04,filtered, and concentrated to leave 3.36 g (95% overall from 10) of the crude nitrile 12. Analysis of 12 by TLC (petroleum ether/ether ( l o l ) ,Rr 0.43) showed one single spot. A dichloromethane (80 mL) solution of 12 (3.36 g 15.6 mmol) was treated with DIBAL (1N, 16 mL) at -78 OC. The reaction was slowly warmed to ambient temperature and TLC (petroleum ether/ether (101)) indicated complete reaction after 2 h. The reaction was then cooled to ice temperature, and aqueous NH4Clwas added dropwise to the vigorously stirred solution. The quenched reaction was stirred at 0 OC for 1h and then acidified with 1 N HCl. The solution was transferred to a separatory funnel and extracted with petroleum ether (2 X 100 mL). The organic layer was then washed with aqueous NaHCOS, water, and saturated brine and then dried over NazS04,filtered, and concentrated to leave 3.38 g (quantitative) of aldehyde 13. Preparationof Aldehyde 15a. A solution of aldehyde 13 (1.69 g, 7.7 mmol) in benzene (40 mL) was treated with methyl (tri-
2316 J. Org. Chem., Vol. 56, No. 7, 1991
phenylphosphorany1idene)acetate (3.63 g, 10.8 "01) and stirred in the dark at room temperature for 2 days. The reaction was concentrated and the reaidue taken up in CH2C12(ca.2 mL). The dichloromethanesolution was then passedthrough a small column of silica (CHZClzas eluent) to remove the polar byproducts. The collected fractions were concentrated, and the crude Wittig olefin was purified by flash chromatography (using a solvent gradient of petroleum ether/ether (30:l to 101)) to leave 1.56 g (73%)of ester olefin 14a as an oil. Olefin 14a was further purified by Kugelrohr distillation (bp 70 OC; 0.3 mmHg) to leave 1.52 g (97% recovery). To olefin 14a (1.49 g, 5.45 "01) in THF (30 mL) at +O "C was added Os04(1.24 g, 4.91 "01). The resulting mixture was allowed to stand at -28 OC for 5 days. The reaction was quenched by bubbling HzS through the solution and stirring at ice temperature for 1 h. The resulting black precipitate was filtered through Celite, and the filtrate was concentrated under reduced pressure. The crude product was purified by flash chromatography (2.5% MeOH/CHC13) to leave 850 mg (51%) of the desired diol. The diol (850 mg, 2.75 mmol) in MeOH (35 mL) and water (11 mL) was treated with NaI04 (625 mg, 2.92 mmol) at 0 "C. TLC (5% MeOH/CHC13) showed complete reaction after 20 min, and the reaction was quenched with the addition of saturated brine (70 mL). The crude aldehyde 15a was extracted into 2 1 petroleum ether/CH2Clz(3 x 100 mL), and the organic layer was dried over NazS04,filtered, and concentrated. Purification by flash chromatography on silica (petroleum ether/ether (3.5:l)) left 634 mg (83%) of aldehyde 15a. Overall yield from 13 was 31% over 3 steps. Preparation of Aldehyde 15b. Following the procedure outlined previously, aldehyde 13 (1.69 g, 7.7 mmol) when treated with ethyl 2-(triphenylphosphoranylidene)propionate (4.88 g, 13.5 mmol) left 1.74 g (79%) of ester olefin 14b after purification by flash chromatography (petroleum ether/ether (301)). Treatment of 14b (1.7 g, 5.89 mmol) with Os04 (1.35 g, 5.30 mmol) left 820 mg (43%) of pure diol after flash chromatography (1.5% MeOH/CHC13). Sodium metaperiodate (575 mg, 2.68 mmol) cleavage of the diol (820 mg, 2.54 mmol) left, after flash chromatography (petroleum ether/ether (41)), 520 mg (70%)of pure aldehyde 15b. Overall yield from 13 was 24%. Preparation of Tetraene 2a. To a solution of aldehyde 15a (367 mg,1.33 "01) in THF (24 mL) stirring at -78 "C was added dropwise a solution of vinyllithium in THF (0.94 M, 1.7 mL). The reaction was allowed to warm slowly to room temperature and stirred for 45 min, at which time TLC (petroleum ether/ether (3:1), Rf 0.27) indicated consumption of 15a. The reaction was diluted with petroleum ether (50 mL) and quenched with aqueous NaHC03. The layers were separated, and the organic layer was washed once with saturated brine. The organic layer was dried over Na@04, filtered, and concentrated to leave the crude allylic alcohol 16a. Purification by flash chromatography (petroleum ether/ether (3:l)) left 241 mg (60%) of 16a. To allylic alcohol 16a (241 mg,0.79 "01) in DMF (7.5 mL) was added DMAP (290 mg, 2.37 mmol) and tert-butyldimethylsilylchoride (180 mg, 1.19 mmol) at room temperature. The reaction was stirred in the dark for 35 h until TLC (petroleumether/ether (lOl),ef0.55) indicated product formation. The reaction as quenched mth the addition of water (4 dram) and stirred for 15 min. The reaction was diluted with pentane (100 ML) and water (25 mL), and the layers were separated. The organic layer was dried over Na&04, filtered, and concentrated. The crude product was purifed by flash chromatography (petroleum ether/ether (151)) to leave 280 mg (84%) of the desired silyl ether. The silyl ether (280 mg, 0.67 mmol) in CHzClz (18 mL) was treated with DIBAL (1 MI 1.47 mL) at -78 "C. The reaction was stirred for 30 min at which time TLC (petroleum ether/ether (101)) indicated consumption of the starting material. The reaction mixture was quenched with aqueous sodium tartrate and extracted with CH2C12(75 mL). The layers were separated and the organic layer dried over NazS04, filtered, and concentrated to leave the crude allylic alcohol, which was taken up in DMF (3.5 mL) and treated with pyridinium dichromate (600 mg, 1.59 mmol) at ice temperature for 30 min. TLC (petroleum ether/ether (lol),R, 0.47) indicated complete reaction. The inorganic salts were removed by filtration, and the filtrate was concentrated to leave the crude allylic aldehyde. A solution of methyltriphenylphosphoniumbromide (480 mg, 1.34 "01) in THF (10 mL) was treated with n-BuLi (1.6M, 0.74 mL).
Sakan et al. The resulting ylide was then reacted with the allylic aldehyde dissolved in THF (ca. 3 mL) at room temperature. The reaction was instantaneous by TLC (petroleum ether/ether (101)) and quenched with aqueous NH4Cl. The crude product was extracted with CHzClz(70 mL) and washed with water. The layers were separated and the organic layer dried over Na@04, filtered, and concentrated. Purification by flash chromatography (CH&12/ petroleum ether (1:2.5)) left 201 mg (79% from the silyl ether) of the tetraene 17a. Diene 17a (201 mg,0.52 m o l ) was treated with a THF solution of n-Bu4NF (0.75 N, 2 mL) at room temperature. The reaction was stirred for 15 min, and TLC (petroleum ether/ether (41), Rf 0.5) indicated loss of the silyl moiety. The reaction was concentrated and purified by flash chromatography (petroleum ethr/ether (5:l)) to leave 140 mg (99%)of allylic alcohol. To a solution of TFAA (108 mL, 0.76 mmol) in CHzC12(11 mL) was added DMSO (75 mL, 1.05 mmol) at -78 "C. A solution of allylic alcohol (140 mg, 0.51 mmol) in CHzC12 (ca. 2 mL) was added to the oxidation solution at -78 OC followed by the addition of Hunig's base (300 pL). The reaction temperature was allowed to slowly warm to 0 "C until TLC (petroleum ether/ether (41)) indicated complete oxidation. The reaction was quenched with aqueous NH4Cland diluted with petroleum ether (100 mL). The organic layer was then treated with 1 N NaOH and vigorously stirred at room temperature for 3 h. The layers were separated and the organic layer dried over NazS04, filtered, and concentrated. Purification by flash chromatography (petroleum ether/ether (15:l)) left 106 mg (76%) of tetraene 2a. Preparation of Tetraene 2b. In a similar fashion to that of aldehyde 15a, reaction of 15b (242 mg, 0.83 mmol) left 235 mg (89%) of allylic alcohol 16b. Treatment of 16b (235 mg, 0.74 "01) with tert-butyldimethylsilyl chloride (180 mg,1.19 mmol) afforded 300 mg (94%) of the desired silyl ether. The silyl ether (300 mg, 0.69 mmol) was treated with DIBAL (lM, 1.53 mL) to leave the allylic alcohol in quantitative yield. Oxidation with PDC (600 mg, 1.59 mmol) followed by Wittig olefination (500 mg, 1.37 mmol) left 257 mg (93%)of tetraene 17b. Deprotection of 17b (257 mg, 0.64 mmol) with n-Bu4NF (0.75 N, 0.5 mL) left 180 mg (98%)of dylic alcohol, which when treated with TFAA (132 pL) left 115 mg (65%) of tetraene 2b. Preparation of Tetraene 2c. A solution of 15a (181 mg, 0.66 mmol) in THF (14 mL) left 127 mg (60%) of allylic alcohol 16c when treated with allylmagnesium bromide (1.1 M, 0.60 mL). with tert-butyldimethylsilyl Treatment of 16c (127 mg,0.40 "01) afforded 148 mg (86%)of the desired chloride (89 mg, 0.58 "01) was treated with silyl ether. The silyl ether (316 mg, 0.73 "01) DIBAL (lM, 216 mL) to leave the allylic alcohol in quantitative yield. Oxidation with PDC (1.0 g, 2.65 mmol) followed by Wittig left 317 mg (>95%) of tetraene olefination (580 mg, 1.59 "01) 17c. Deprotection of 17c (317 mg, 0.79 mmol) with n-Bu,NF (0.75 N, 5.0 mL) left 214 mg (95%) of allylic alcohol. Treatment of the allylic alcohol (39 mg, 0.14 mmol) with TFAA (29 pL) left 29 mg (74%) of tetraene 2c. Preparation of Tetraene 2d. In an analogous manner to that of aldehyde 15a, a solution of 15b (188 mg, 0.65 mmol) in THF (14 mL) left 172 mg (80%)of allylic alcohol 16d when treated with allylmagnesium bromide (1.1 MI 0.60 mL). Treatment of 16d (172 mg, 0.52 mmol) with tert-butyldimethylsilyl chloride (150 mg, 0.98 mmol) afforded 196 mg (68%) of the desired silyl ether. The silyl ether (196 mg, 0.44 mmol) was treated with DIBAL (lM, 0.97 mL) to leave the allylic alcohol in quantitative yield. Oxidation with PDC (400 mg,1.06 m o l ) followed by Wittig olefination (315 mg, 0.86 mmol) left 123 mg (67%) of tetraene 17d, which upon deprotection with n-Bu,NF (0.75 N, 1.5 mL) left 81 mg (89%) of allylic alcohol. Treatment of the allylic alcohol (40 mg, 0.13 mmol) with TFAA (29 p L ) left 28 mg (70%) of tetraene 2d. Cycloaddition Reactions of Substituted Tetraenes 2a-d. Method A. Thermal Cycloaddition of Tetraene 2a. A solution of 2a (35 mg, 0.129 mmol) in dry benzene (30 mL) was added to an oven-dried ampule. The solution was then treated with BHT (15 mg, 0.068 mmol) and degassed three times (liquid Nz) under high vacuum. The ampule was sealed under vacuum and immersed in a 120 OC oil bath for 4 days followed by a 140 "C oil bath for 1 day. The crude reaction mixture was purified by column chromatography on silica with petroleum ether followed by a
J. Org. Chem. 1991,56,2317-2322 solvent gradient of petroleum ether/ether (201 and 101) to leave 3a-a-trans (17%), and 3a-B-trans pure cycized 3a-a-cis (a%), (19%). 3a-a-cis (6OO-MHz) 'H NMR (CDCld: 5.53 (1H, m), 5.31 (1 H, m), 3.51 (1H, d, J = 14.1 Hz), 3.15 (1H,dq, J = 14.1,l.l Hz), 2.81 (1 H, m, J 3 p = 5.9 Hz), 2.45 (1H, m), 2.34 (1H, m), 1.86 (3 H, d, J = 1.1 Hz), 0.97 (3 H, 8 ) . Sa-B-trans (600-MHz) 'H NMR (CDC13): 5.49 (1H, m), 5.45 (1H, m), 3.29 (1H, d, J = 14.7 Hz), 3.00 (1H, d, J = 14.7 Hz), 2.69 (1H, ddd, J = 14.0, 11.0,3.7 Hz), 2.39 (1H, m, J3/8= 13.9 Hz), 2.36 (1H, quint), 1.85 (3 H, s), 1.00 (3 H, 9). 3a-a-trans (300-MHz) 'H NMR (CDC13): 5.56 (1H, m), 5.18 (1H, m), 3.50 (1H, d, J = 14.9 Hz), 3.13 (1 H, d, J = 14.9 Hz), 3.13 (1H, ddq, J = 14.9, 1.7, 1.2 Hz), 2.55 (1 H, m, J3 = 9.7 Hz), 2.42 (1H, dddd, J = 11.4,9.7, 3.6,1.7 Hz), 2.31 (1 m), 1.80 (3 H, d, J = 1.2 Hz),1.09 (3 H, 8 ) . Thermal Cycloaddition of Tetraene 2b. By use of the procedure outlined previously, 2b gave 3b-a-cis (49%),3b-a-trans (36%), and 3b-a-trans (15%) after purification by column chromatography on silica. 3b-a-cis (300-MHz) 'H NMR (CDC13): 5.25 (1H, bs), 3.50 (1H, d, J = 14.6 Hz), 3.15 (1H, dq, J = 14.6, 1.3 Hz), 2.61 (1H, m, J3/8= 4.9 Hz), 2.32 (1H, dddd, J = 11.9, 4.9, 2.4 Hz), 2.31 (1H, m), 1.81 (3 H,d, J = 1.3 Hz), 1.59 (3 H, be), 0.93 (3 H, 9). Sb-b-trans (600-MHz) 'H NMR (CDClJ: 5.36 (1H, bs), 3.30 (1H, d, J = 15.1 Hz), 3.01 (1H, d, J = 15.1 Hz), 2.79 (1H, ddd, J = 14.0, 10.6,3.7 Hz), 2.37 (1H, quint), 2.33 (1 H, m, Js18= 14.0 Hz), 1.84 (3 H, s), 1.66 (3 H, b s), 1.04 (3 H, 9). 3b-a-trans (300-MHz) 'H NMR (CDCl3): 5.48 (1H, bd, J = 6.4 Hz), 3.30 (1H, d, J = 13.1 Hz), 3.19 (1H, d, J = 13.1 Hz), 2.78 (1 H, b quint), 2.27 (1 H, m), 1.72 (3 H, s), 1.50 (3 H, b s), 1.31 (3 H, 8 ) . Thermal Cycloaddition of Tetraene 2c. In an analogous manner to that above, thermal cycloaddition of 2c yielded after purification 3c-a-cis (27%), 3c-a-trans (38%), b-@-cis(13.5%), and b-8-tmns (12%). b-@-cis(6OO-MI-h)'H N M R (CDClJ: 5.55 (1H, m), 5.48 (1H, m), 3.54 (1H, d, J = 13.2 Hz),3.22 (1H, d, J = 13.6 Hz), 2.82 (1 H, b s), 2.22 (1 H, bs), 1.80 (3 H, s), 1.40 (3 H, s), 1.17 (3 H, 9). ~ C - C Y - C (6oo-MH~) ~S 'H NMR (CDClJ: 5.40 (1H, m), 5.29 (1H, m), 3.85 (1H, d, J = 14.3 Hz), 3.05 (1H, dq, J = 14.3, 1.1Hz), 2.37 (1H, b t), 2.34 (1 H, b q), 1.92 (3 H, d, J = 1.1 Hz),1.12 (3 H, s), 0.99 (3 H, 8 ) . 3c-@-trans(600-MHz) 'H NMR (CDC13): 5.55 (1H, m), 5.17 (1H, m), 3.58 (1H, d, J = 15.1 Hz),3.15 (1H, dq, J = 15.1, 1.5 Hz), 2.65 (1 H, m), 2.28 (1 H, m), 1.85 (3 H, d, J = 1.5 Hz), 1.08 (3 H, s), 1.03 (3 H, 8). 3c-a-trans (600-MHz) 'H NMR (CDCl3): 5.47 (1 H, m), 5.15 (1 H, m), 3.68 (1 H, d, J = 16.2 Hz), 3.15 (1 H, m), 3.09 (1 H, dq, J = 16.2, 1.8 Hz), 2.31 (1 H, quint, J = 2.9 Hz), 1.82 (3 H, d, J = 1.8 Hz), 1.10 (3 H, s), 0.94 (3 H, a).
k,
2317
Thermal Cycloaddition of Tetraene 2d. In a similar fashion to that above, 2d afforded 3d-a-trans (70%) after purification. 3d-a-trans (300-MHz) 'H NMR (CDCl,): 5.16 (1H, m), 3.85 (1 H, d, J = 14.4 Hz), 3.05 (1 H, dq, J = 14.4, 1.4 Hz), 2.33 (1 H, q, J = 2.9 Hz), 2.14 (1H, b d, J = 6.0 Hz), 1.90 (3 H, d, J = 1.4 Hz), 1.60 (3 H, b s), 1.06 (3 H, s), 0.98 (3 H, 9). Method B. Lewis Acid Cycloaddition of Tetraene 2d. A solution of 2d (40 mg, 0.145 mmol) in dry benzene (25 mL) was treated slowly with dimethylammonium chloride (1.0 M, 0.15 mL, 0.145 mmol) at room temperature. After the addition was complete, TLC (80:7 petroleum ether/ether) indicated complete consumption, and the reaction was quenched with saturated NaHCO, (5 mL). After 30 min, the reaction was diluted with petroleum ether (ca. 15 mL) and transferred into a separatory funnel. The organic layer was separated and the aqueous portion further estracted with petroleum ether (5 X 5 mL). The combined organic layers were then washed with brine, dried over Na2S04, filtered, and concentrated. Flash chromatography on silica gel (807 petroleum ether/ether) provided pure 3d-a-cis (85%). 3d-a-cis (600-MHz) 'H NMR (CDCl,): 5.33 (1 H, b s), 3.70 (1 H, d), 3.09 (1 H, dq), 3.04 (1 H, b s), 2.31 (1 H, quint), 1.82 (3 H, d), 1.64 (3 H, m), 1.11 (3 H, s), 0.97 (3 H, 8 ) . Epimerization Studies on Cycloadducts 3 a - a d s and 3aa-trans. A methanolic solution of pure or enriched mixtures of 3a-a-cis or 3a-a-trans were treated with 1 M NaOMe at 58 "C for 18 h. The reaction was cooled to ambient temperature and diluted with petroleum ether (20 mL). The organic mixture was quenched with saturated NaHC03 and the layers separated. The organic phase was then washed with brine, dried over Na2S04, and concentrated. The crude reaction was examined by proton NMR to determine the product ratios.
Acknowledgment. The 300- and 600-MHz spectra were obtained at CMU by use of the facilities supported by the National Institutes of Health. We are indebted to Dr. A. A. Bothner-by for his help in obtaining the 600-MHz spectra. We wish to also thank t h e donors of the Ford Motor Co., administered by CMU, for support of this research. Supplementary Material Available: X-ray experimental procedures and coordinatesfor hydrogen and non-hydrogen atoms, anisotropic thermal parameters, bond distances and angles, and torsion angles for 3a-a-cis and 3a-@-trans;approximate coordinates for the ordered molecular 3b-fl-tran.s (16 pages).Ordering information is given on any current masthead page.
Asymmetric Synthesis of (S)-ZearalenoneDimethyl Ether, an Orsellinic Acid Type Macrolide Guy Solladi&**tM. Carmen Maestro,*Almudena Rubio,+ Concepcion Pedregal,+J M. Carmen Carreiio,*J and Jose L. Garcia Ruano*** Ecole Europeenne des Hautes Etudes des Industries Chimiques (URA du CNRS 466), 67008 Strasbourg, France, and Departamento de Quimica (C-Z), Uniuersidad Autonoma, Cantoblanco, 28049 Madrid, Spain Received July 18, 1990 The synthesis of (S)-zearalenone dimethyl ether is described. The chiral part of the molecule was obtained by asymmetric synthesis monitored by a chiral sulfoxide group and introduced in the very last steps of the synthesis.
Zearalenone (la) is a naturally occuring 14-membered orsellinic acid type macrolide' with anabolic and uterotropic activity. Several total syntheses of racemic zearalenone were carried out during t h e last 20 years,2 and a 'Ecole Europ€enne des Hautes Etudes des Industries Chimiques. t Universidad
Autonoma.
chiral synthesis from a natural product was recently published.2j (1) (a) Stob, M.; Baldwin, R. S.; Tuite, J.; Andrew, F. N.;Gdette, K. G. Nature (London) 1962,196,1318. (b) Mirocha, C. J.;Christensen, C. M.; Nelson, G. H. Appl. Microbiol. 1967, 15, 497. (c) Urry, W. H.; Weheistar, H. L.; Hodge, E. B.; Hidy, P. H. Tetrahedron Lett. 1966, 3109.
OO22-3263/91/ 1956-2317$02.50/0 0 1991 American Chemical Society
